Dopaminergic neurons in the brain are thought to play an important role in the etiology of schizophrenia. One theory of schizophrenia suggests that it is due to an imbalance of dopamine in certain brain areas. The drug cocaine enhances the action of dopamine in the brain. Humans who take cocaine in high doses for a prolonged period of time may suffer symptoms of pro longed depression and apathy similar to the negative symptoms seen in schizophrenic patients. Similarly, the repeated administration of high doses of cocaine in rats can produce a decrease in locomotor activity and a lack of 'the usual sensitization state seen with lower dose stimulant drug challenge. In earlier studies, we evaluated the effects of cocaine administration on the activity of tyrosine hydroxylase in five brain regions of rats. Cocaine, administered in a dose of 10 mg/kg intraperitoneally, given twice a day for seven days, produced a significant increase in tyrosine hydroxylase activity of approximately 50% in the ventral tegmental area at six and twelve weeks after the last cocaine administration. Similar studies have been performed measuring the in vivo hydroxylation of tyrosine in these brain regions. Cocaine produced a significant decrease in tyrosine hydroxylation in the frontal cortex (30%) and nucleus accumbens (34%) compared with saline treated rats six weeks after the last injection, with no significant differences after two week& These data suggest that cocaine increases tyrosine hydroxylase activity in the ventral tegmental area in response to decreased synthesis of dopamine in the frontal cortex and nucleus accumbens. Recently, we have initiated studies to measure tyrosine hydroxylase activity in human brain tissue. Tyrosine hydroxylase activity can be detected in human cortical tissue with the use of concentrator-filtration system (Centricon, Amicon). However, this activity is relatively low (twice blank) and additional studies are in progress to enhance the sensitivity of the assay.